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Molecular network pathways and functional analysis of tumor signatures associated with development of resistance to viral gene therapy

Cancer Gene Therapy volume 19, pages 38–48 (2012)Cite this article

Abstract

Replication-competent attenuated herpes simplex viruses have proven effective in killing many cancer cell lines. However, determinants of resistance to oncolytic therapy are mostly unknown. We developed viral therapy-resistant cells and examined changes in gene-expression pattern compared with therapy-sensitive parental cells. Colon cancer cell line HT29 and hepatoma cell line PLC5 were exposed to increasing concentrations of virus G207. Therapy-resistant cells were isolated and grown in vitro. Tumorigenicity was confirmed by ability of cell lines to form tumors in mice. Human Genome U133A complementary DNA microarray chips were used to determine gene-expression patterns, which were analyzed in the context of molecular network interactions, pathways and gene ontology. In parental cell lines, 90–100% of cells were killed by day 7 at 1.0 multiplicity of infection. In resistant cell lines, cytotoxicity assay confirmed 200- to 400-fold resistance. Microarray analysis confirmed changes in gene expressions associated with resistance: cell surface proteins affecting viral attachment and entry, cellular proteins affecting nucleotide pools and proteins altering apoptotic pathways. These changes would decrease viral infection and replication. Our study identifies gene-expression signatures associated with resistance to oncolytic viral therapy. These data provide potential targets to overcome resistance, and suggest that molecular assays may be useful in selecting patients for trial with this novel treatment.

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Acknowledgements

This work was supported by Grants R01CA75416 and R01CA72632 from the National Institutes of Health (to YF), MBC-99366 from the American Cancer Society (to YF) and a grant from the Flight Attendant Medical Research Institute (FAMRI; to YF).

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Author notes

  1. T-J Song and D Haddad: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    T-J Song, D Haddad, P Adusumilli, T Kim, B Stiles, M Hezel, N D Socci & Y Fong

  2. Department of Surgery, New York College of Medicine, Korea University, Seoul, South Korea

    T-J Song

  3. Institute for Biochemistry and Virchow Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany

    D Haddad

  4. Department of Bioinformatics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    N D Socci

  5. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    M Gönen

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  1. T-J Song
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Correspondence to Y Fong.

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Song, TJ., Haddad, D., Adusumilli, P. et al. Molecular network pathways and functional analysis of tumor signatures associated with development of resistance to viral gene therapy. Cancer Gene Ther 19, 38–48 (2012). https://doi.org/10.1038/cgt.2011.64

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